Few chemical reactions have reached the prominence of aldol-type reactions in the synthesis of complex molecules (Mukaiyama, 1982; Kim et al., 1991; Heathcock, 1984). The classical aldol reaction is highly atom economic (Trost, 1995) but suffers from poor chemo- and regioselectivity. In current practice, aldol reactions typically employ a preformed enolate, enol, or equivalent; an example is the Mukaiyama reaction, which employs an enol silyl ether. These reactions generally provide greater selectivity, but require stoichiometric amounts of base and/or adjunct reagents (e.g. silylating agents), thus decreasing the atom efficiency of the process.
Most asymmetric versions of the aldol reaction reported to date rely upon the use of chiral auxiliaries (Seyden-Penne, 1995). Mukaiyama-type processes using asymmetric catalysts have also been reported (Johnson et al., 2000; Carreira, 1998; Mahrwald, 1999; Gröger et al., 1998; Nelson, 1998; Bach, 1994); as noted above, these require prior stoichiometric formation of the nucleophile. Methods for direct catalytic asymmetric aldol addition, without prior stoichiometric formation of the nucleophile, are thus being sought. Processes employing both biological-type (e.g. catalytic antibodies) (Machajewski et al., 2000; Takayama et al., 1997; Hoffmann et al., 1998) and non-biological-type (Yoshikawa et al., 1999; Shibasaki et al., 1999; List et al., 2000; Notz et al., 2000; Agami et al., 1987; Nakayawa et al., 1985) catalysis have been reported. In all of these cases, however, significant excesses of the donor and/or large amounts of catalyst must be employed, and unbranched aldehyde substrates remain problematic.
The Henry (nitro-aldol) reaction (see e.g. Luzzio et al.) is also a fundamental C—C bond forming reaction which generates stereogenic centers. There are very few examples to date of catalytic asymmetric nitroaldol reactions. Shibasaki et al. have carried out such reactions using chiral heterobimetallic (rare earth-alkali metal) catalysts, and Jorgensen et al. have reported the catalytic asymmetric aza-Henry reaction of silyl nitronates with imines. However, the use of silyl nitronates as nucleophiles undermines the atom economy of the reaction.